Implant device with a retinoid for improved biocompatibility

ABSTRACT

An implant device is provided which incorporates a retinoid for improving the biocompatibility of the device in tissue. The device may be bioerodible for the purpose of systemically or locally releasing a therapeutic agent in tissue or it may be a permanent implant which includes a surface treated with a retinoid for increasing the biocompatibility thereof.

This application is a continuation of Ser. No. 09/587,485, filed Jun. 5,2000, now U.S. Pat. No. 6,306,426.

The present application is a continuation-in-part of U.S. Ser. No.09/356,074 filed Jul. 16, 1999, now U.S. Pat. No. 6,110,485 which is acontinuation of U.S. Ser. No. 09/150,990 filed Sep. 10, 1998, now U.S.Pat. No. 6,074,661 which is a continuation of U.S. Ser. No. 08/908,094filed Aug. 11, 1997, now abandoned.

The present invention is generally related to implantable devices and ismore particularly directed to an implantable prosthesis having improvedbiocompatibility. Still more particularly, the present invention isdirected to an implantable device having improved biocompatibility whileproviding systemic release of a therapeutic agent in tissue.

It should be appreciated that physiological compatibility andbiocompatibility are common problems for both implants for providing asystemic, or local, release of the therapeutic agent and for prosthesis,i.e., implants, utilized for functional or cosmetic reasons, or both.

It should be appreciated that the term “biocompatible” in the presentapplication relates to a foreign object that can be left in a human oranimal body for an extended or an indefinite period without causing anyadverse physiological action.

The functional biocompatibility of an implant or device, is, of course,determined by the chemical and surface properties of the implant and itscomponents. The general structure of a device, including mechanicalstrength, elasticity, flexibility, fatigue resistance, chemicalinertness, impermeability to water, resistance to acid, etc., allcontribute to biocompatibility which, of course, also depends upon thetype of tissue into which the implant is to be inserted. Mostimportantly, the surface of the implant in contact with body tissuesshould also exhibit resistance to immunological attack, cell adhesion,pannus formation, etc.

Undesirable properties which can result from tissue interacting with thesurface may significantly affect the efficiency of the implant and becounteractive to the intended use of the implant in certain medicaldevices, for example, sustained or controlled drug release devices.

The use of a sustained, or controlled release system has a well knownadvantage of providing an active agent at a relatively constant level ofconcentration in tissue. Sustained drug release systems have beenutilized in a great number of applications including drug release intothe vitreous for endophthalmitis and other vitreoretinal disorders withthe use of antibiotics and a fungal agent, antineoplastic drugs andanti-inflammatory agents.

Unfortunately, in many instances, particularly where the implant isintended to remain in contact with tissue for extended periods of time,various problems associated with the physiological and chemicalstability and compatibility with respect to various of the contactedtissues and biological fluids occurs. This is true even though theimplant may function properly in its sustained or controlled release ofthe active agent.

For example, biomaterial such as a synthetic polymer, when contactedwith blood, rapidly forms an adsorbed protein layer. Subsequently,conformational alterations and completing of proteins which may occurwhich activate defense mechanisms such as coagulation, plateletadhesion, and aggregation, white cell adhesion, etc.

In eye tissue, an implant may cause superficial vascularization of thecornea with infiltration of granulation tissue. Biodegradable polymersmay cause mild foreign body reactions which include inflammation in thevitreous.

Implanted biomaterials will cause a typical foreign body reaction withfibrinous membrane formation. A fibrinous membrane will surround andencapsulate the implant. Contraction of this fibrous capsule can rangefrom transient pain to serious sequelae depending upon the location.Fibrinous infiltration of the vitreous with a prominent inflammatoryresponse can lead to traction retinal detachment, disruption of theretinal pigmented epithelium or breakdown of the blood retinal barrier.Tissue and organ adhesions may develop as a result of the fibrinousinflammation. Intraocular implants can also cause cataract formation.Irisciliary body adhesions would seriously effect the homeostasis ofocular tension. Implants, being foreign objects, may cause acute andchronic inflammation. Tissue necrosis and scarring may result as well asneovascularization. Biopolymers may often be antigenic and elicitallergic or other adverse events. In the case of an implantable materialin the vasculature or heart thrombus formation and embolus may occur.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the present invention, animplantable device is provided for systemic, or local, release of atherapeutic agent in tissue. The device generally includes a therapeuticagent along with a carrier sized for insertion into tissue in which thesystemic release of a therapeutic agent is desired, the carrierincluding means for providing sustained or controlled release of thetherapeutic agent.

In addition, retinoid means, present in the carrier, is provided forimproving biocompatibility of the device in the tissue.

As will be described in detail hereinafter, this hereinbeforeunrecognized property of a retinoid substantially reduces or preventsundesirable attributes which can result from tissue interacting with thesurface of the implantable device.

More particularly, in accordance with the present invention, theretinoid means may comprise a retinoid receptor agonist and thetherapeutic agent, carrier, and retinoid means, may be homogeneous. Thishomogeneity provides for ease of manufacturing through the use of simpleextrusion techniques or injection molding.

Specifically, in accordance with this embodiment of the presentinvention, the means for providing time release of the therapeutic agentmay comprise a biodegradable polymer, such as, for example, apoly(lactic acid) and poly(lactide-co-glycolide).

More particularly, in accordance with one embodiment of the presentinvention, the carrier may be sized for implanting into a sclera and theretinoid receptor agonist may be a retinoid acid, for example, selectedfrom the group of naturally occurring retinoids such as Vitamin A(retinol), Vitamin A aldehyde (retinal), Vitamin A acid (retinoic acid)and their synthetic and natural congeners. These would include but notbe limited to the isomers all trans; 9-cis; 11-cis; 13-cis; 9, 11-dicis,and 11, 13-dicis as well as physiologically compatible ethers, esters,amides and salts thereof. The 7, 8-dihydro and 5, 6-dihydro congeners aswell as etretinate are also acceptable for the invention.

Compounds that intrinsically or upon metabolism possess the physiologicproperties of retinoids are also included within the scope of thisinvention. These would include synthetic and natural retinoid compoundshaving affinity to nuclear retinoic acid receptors (RARs) and retinoid Xreceptors (RXRs).

More particularly, the retinoid receptor agonist may beethyl-6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, or6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinic acid, orp-[(E)-2-(5,6,7,8-tetrahydro-,5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoicacid.

Corresponding to the device of the present invention, a method inaccordance with the present invention for improving biocompatibility ofan implant in tissue generally includes the steps of providing atherapeutic agent, providing a carrier sized for insertion into tissuein which release of the therapeutic agent is desired, incorporating atherapeutic agent into a carrier in a manner enabling sustained orcontrolled release of the therapeutic agent and incorporating a retinoidinto the carrier in an amount effective for improving biocompatibilityof the carrier in the tissue.

Many conditions and diseases are treatable with stents, catheters,cannulae and other devices inserted into the esophagus, trachea, colon,biliary tract, urinary tract and other locations in the body, or withorthopedic devices, implants, or replacements. It would be desirable todevelop devices and methods for reliably delivering suitable agents,drugs or bioactive materials directly into a body portion during orfollowing a medical procedure, so as to treat or prevent such conditionsand diseases, for example, to prevent abrupt closure and/or restenosisof a body portion such as a passage, lumen or blood vessel.

As a particular example, it would be desirable to have devices andmethods which can deliver an antithrombic or other medication to theregion of a blood vessel which has been treated by PTA, or by anotherinterventional technique such as atherectomy, laser abllation, or thelike. It would also be desirable that such devices would deliver theiragents over both the short term (that is, the initial hours and daysafter treatment) and the long term (the weeks and months aftertreatment). It would also be desirable to provide precise control overthe delivery rate fro the agents, drugs or bioactive materials, and tolimit systemic exposure to them. This would be particularly advantageousin therapies involving the delivery of a chemotherapeutic agent to aparticular organ or site through an intravenous catheter (which itselfhas the advantage of reducing the amount of agent needed for successfultreatment), by preventing stenosis both along the catheter and at thecatheter tip. A wide variety of other therapies could be similarlyimproved.

Another embodiment of the present invention includes an implantabledevice, specifically a surgically implantable prosthesis in combinationwith retinoid means for improving the biocompatibility of theprosthesis. More specifically, the retinoid means may be present in theform of a film on the prosthesis or, alternatively, bonded to a surfaceof the prosthesis.

Other implants to be considered as part of the present invention includebiocompatible stents such as described in U.S. Pat. Nos. 5,342,348 and5,554,381, biocompatible bone pins such as described in U.S. Pat No.4,851,005, biodegradable/biodegradable joint prosthesis such asdescribed in U.S. Pat. No. 6,007,580, biodegradable birth controldevices such as described in U.S. Pat. No. 5,733,565, biodegradableimplants for treatment of prostate cancer or any biodegradable drugdelivery system.

All of the hereinabove referenced patents are to be incorporatedherewith, including all drawings and specifications, by this specificreferences thereto.

As hereinabove noted, the retinoid means may comprise a retinoidselected from the group of naturally occurring retinoids such as VitaminA (retinol), Vitamin A aldehyde (retinal), Vitamin A acid (retinoicacid) and their synthetic and natural congeners. These would include butnot be limited to the isomers all trans; 9-cis; 11-cis; 13-cis; 9,11-dicis, and 11, 13-dicis as well as physiologically compatible ethers,esters, amides and salts thereof. The 7, 8-dihydro and 5,6-dihydrocongeners as well as etretinate are also acceptable for the invention.

Compounds that intrinsically or upon metabolism possess the physiologicproperties of retinoids are also included within the scope of thisinvention. These would include synthetic and natural retinoid compoundshaving affinity to nuclear retinoic acid receptors (PARs) and retinoid Xreceptors (RXRs).

Importantly, the present invention encompasses a method for improvingbiocompatibility of a surgically implantable prosthesis with the methodcomprising the step of combining a retinoid with the prosthesis. Moreparticularly, the step may include disposing a film of retinoid on theprosthesis or, embedding retinoid, to the surface of the prosthesis. Theretinoid may comprise a retinoid, as hereinabove noted, and be selectedfrom the group of naturally occurring retinoids such as Vitamin A(retinol), vitamin A aldehyde (retinal), Vitamin A acid (retinoic acid)and their synthetic and natural congeners. These would include but notbe limited to the isomers all trans; 9-cis; 11-cis; 13-cis; 9, 11-dicis,and 11, 13-dicis as well as physiologically compatible ethers, esters,amides and salts thereof. The 7, 8-dihydro and 5,6-dihydro congeners aswell as etretinate are also acceptable for the invention.

Compounds that intrinsically or upon metabolism possess the physiologicproperties of retinoids are also included within the scope of thisinvention. These would include synthetic and natural retinoid compoundshaving affinity to nuclear retinoic acid receptors (RARs) and retinoid Xreceptors (RXRs).

BRIEF DESCRIPTION OF THE DRAWINGS

The advantages and features of the present invention will be betterunderstood by the following description when considered in conjunctionwith the accompanying drawings in which:

FIG. 1 is an implantable device in accordance with the one embodiment ofthe present invention, specifically a retinal plug, for providing localdelivery to the intraocular tissues of a therapeutic agent;

FIG. 2 is a diagram showing the positioning of the retinal plug shown inFIG. 1 in an eye through the sclera and pars planar;

FIG. 3 is a perspective view of an alternative embodiment in accordancewith the present invention, specifically a surgically implantableprosthesis such as a cardiac valve component coated with a film ofretinoid;

FIG. 4 is a perspective view of a stent coated with a film of retinoid;

FIG. 5 is a cross section view of a stud implant coated with a film ofretinoid;

FIG. 6 in a side view of a joint prosthesis incorporating a retinoid inaccordance with the present invention;

FIG. 7 is a drawing showing the encapsulation of a placebo plug 28 daysafter insertion into the vitreous through sclera. The plug is comprisedof polylactic acid. The plug disappears during the processing of the eye(A). The tissues surrounding the plug were stained with PAS and show afibrous capsule surrounding the area (B) where the placebo waspreviously located. The capsule that surrounded the polylactic acid plugshows a very prominent inflammatory response with inflammatory cellinfiltration (C); and

FIG. 8 is a drawing showing the encapsulation of a retinoid containingplug 28 days after insertion. The polylactic acid plug contained 10% byweight of the retinoid 6-[(4,4-dimethyl thiochroman-6-yl) ethynyl]nicotinic acid (AGN 190299). The plug disappears in the processing ofthe eye (A). The tissues surrounding the retinoid containing plug werestained with PAS. The figure shows that the capsule surrounding theAGN190299 plug (B) has very little fibrous inflammation (C).

DETAILED DESCRIPTION

Turning to FIGS. 1 and 2, there is shown an implantable device 10 forproviding systemic release of a therapeutic agent in tissue. Device 10is representative of a great number of devices for systemic release of atherapeutic agent. This specific embodiment 10 is a sterile, bioerodibleplug for the intraocular delivery of pharmaceutically active compounds.Placement of the device 10 is illustrated in FIG. 2 as it may beinserted into an eye 12 specifically, the sclera 14 proximate the lens16 and iris 18 for release of the drug into the sclera, choroid, retinaand vitreous cavity. By way of example, the retinal plug, or device, 10,may have a weight of about 0.5 to about 10 milligrams, have a diameterof about 0.5 and about 2 millimeters and a length of between one and 12millimeters. A hole 20 through a proximal end 22 of the device 10enables a suture 24 to be used for securing the device 10, as shown inFIG. 2, with a distal end 26 thereof protruding into a vitreous cavity30.

Any suitable therapeutic agent may be utilized. The diversity oftherapeutic agents that can be delivered by the present invention isgreat and known to those skilled in the art. Examples include but arenot limited to antibiotics, antifungals and antivirals such aserythromycin, tetracycline, aminoglycosides, cephalosporins, quinolones,penicilins, sulfonamides, ketoconazole, miconazole, acyclovir,ganciclovir, azidothymidine, interferon; anticonvulsants such asphenytoin and valproic acid; antidepressants such as amitriptyline andtrazodone; antiparkinsonism drugs; cardiovascular agents such as calciumchannel blockers, antiarythmics, beta blockers; antineoplastics such ascisplatin and methotrexate, corticosteroids such as dexamethasone,hydrocortisone, prednisolone, and triamcinolone; NSAIDs such asibuprofen, salicylates indomethacin, piroxicam; Hormones such asprogesterone, estrogen, testosterone; growth factors; carbonic anhydraseinhibitors such as acetazolamide; prostaglandins; antiangiogenic agents;neuroprotectants; other drugs known to those skilled in the art tobenefit from controlled or sustained release from implantable devices orcombinations thereof.

These active agents may be incorporated into a bioerodible polymer suchas a poly ester, poly (ortho ester), poly (phosphazine), poly (phosphateester), poly-caprolactone, poly (hydroxybutyric acid), natural polymersuch as gelatin or collagen, or a polymeric blend. In addition, thepresent invention may also improve the biocompatibility of non-erodiblepolymeric implants.

Importantly, a retinoid is incorporated into the device 10 for improvingthe biocompatibility thereof. All of the components of the device 10 areextruded as a homogeneous system in the shape of a plug.

The device 10 may be optimized to resist sclera and choroidal erosion inorder to prevent disintegration or fragmentation of the plug 10 into thevitreous cavity 30. This may be accomplished, as is well known in theart, by altering the surface, finish of the plug 10, coating the plugwith another biodegradable semipermeable polymer, or the addition ofanother polymer to the blend. Because the plug is a homogeneous system,ease of manufacture is provided through simple extrusion techniques orinjection molding.

The mechanism and rate of drug release may be controlled by the choicepolymer, polymer molecular weight, polymer crystallinity, copolymerratios, processing conditions, surface finish, geometry, excipientaddition, and polymeric coatings, with the drug being released from thedevice 10 by diffusion, erosion, dissolution or osmosis.

The fabrication of various sclera plugs and the mechanism of controllingthe drug release is well known in the art as set forth in numerouspublications such as, for example, “Sclera Plug of BiodegradablePolymers for Controlling Drug Release in Vitreous”, Mototane Hashizoe,Archophthalmol/Volume 112, page 1380-1384, October, 1994; “A New VitrealDrug Delivery Systems Using an Implantable Biodegradable PolymericDevice”, Hideya Kimura et al, Investigative Ophthalmology and VisualScience, Volume 35, page 2815-2819, May, 1994, and U.S. Pat. No.5,466,233, all of which are incorporated herein in their entirety forthe purpose of describing sclera plug manufacture, use and mechanisms.

All of the active ingredients utilized in the plug device 10 are presentin a therapeutic effective amount which is calculated to achieve andmaintain a therapeutic level in the vitreous cavity and introduced bythe vitreous plug. Naturally, the therapeutic amount will vary with thepotency of the active agent, the rate of release by the plug device 10.

The amount of incorporated retinoid will depend on the potency andreceptor selectivity of the retinoid employed as well as the releaserate of the retinoid from the specific implant. Typically, the amount ofretinoid employed represents 0.001% to 50%, more typically from 0.01 to20%

Retinoic acid receptor agonists have been utilized for preventingproliferation of retinal pigment epithelium, see copending U.S. patentapplication Ser. No. 08/383,741, entitled “Method of PreventingProliferation of Retinal Pigment of Epithelium by Retinoic Acid ReceptorAgonists”, filed in the name of Campochiaro and is to be incorporatedherewith in its entirety for describing the use of retinoic acidactivity in the vitreous cavity 30.

Importantly, it has been discovered that the use of retinoids canimprove the biocompatibility of the device 10 in tissue. While theretinoid may be incorporated into the device as a component of thehomogeneous mass, as hereinabove described in connection with the plugdevice 10, the retinoid may also be used to advantage for improvingbiocompatibility when disposed as a film 40 on an implanted device 42 asshown in FIG. 3. The device 42 is a component for a cardiac valve as isdescribed in U.S. Pat. No. 5,370,684 which is to be incorporatedherewith in its entirety in describing typical implantable devices 42suitable in combination with the retinoid for improving biocompatibilitythereof. In addition, this patent is to be incorporated herein by thespecific reference thereto for the purpose of coating or embeddingtechniques suitable for bonding the retinoid to the surface 44 of theimplant 42.

When applied as a film 40 or imbedded into a surface 44 of the implant42, the retinoid may be incorporated in amounts depending on the potencyand receptor selectivity of the retinoid employed as well as the releaserate of the retinoid from the specific implant.

With reference to FIG. 4 there is shown an endovascular stent 80comprising a single helically wound strand 82 and a pair ofcounter-wound filaments 84, 86. Coatings 90,92,96 respectively disposedon the strand 82 and filaments 84, 86 improves the biocompatibility ofthe stent 80 as hereinabove described in connection with the implant 42shown in FIG. 3. Alternatively, the retinoid may be embedded into thestrand 82 and filaments 84, 86.

The stent 80 may provide delivery of therapeutic and other substances toa location within a patients' vascular system. (not shown)

The endovascular stent comprises a tubular structure having an initialdiameter and being expandable from the initial diameter to an enlargeddiameter. The filaments 84, 86, providing a delivery matrix, areinterlaced with the tubular structure and expandable therewith from theinitial diameter to the enlarged diameter. A bioactive substance isreleasably contained within the filament 84, 86 of the delivery matrix,and is released from said matrix when exposed to the conditions presentin the vascular system.

The tubular structure may be composed of an elastic material, such as anelastomer polymer, whereby the tubular structure may be initiallyconstrained to set initial diameter and thereafter released to saidenlarged diameter, Alternatively, the tubular structure could becomposed of a non-plastic material, whereby the tubular structure may beexpanded from the initial diameter to the typically using a balloondilatation catheter.

The various specific designs for the tubular structure exist, includinga helical structure where the filament of the delivery matrix is counterwoven with a helical strand of the tubular structure, a helicalstructure where the filament is laminated to a helically wound strand ofthe tubular structure, and a perforated cylinder where the filament ofthe delivery matrixes interwoven through perforations in the cylinder.

The filaments 84,86 of the delivery matrix may be porous andsubstantially non-erodible, where the bioactive substance is absorbed orimpregnated therein and released over time. Alternatively, the filamentwill be composed of the material which is erodible within the vascularenvironment, where the bioactive substance is contained or dispersed inthe filament and released as the filament material erodes. When anerodible material is used, the retinoid in incorporated therein ashereinabove described.

With reference to FIG. 5 there is shown in sectional side elevation, asurgical implant kit 100 including a stud 102 disposed within a hole 104drilled into a bone 106 with a pin 108 driven into a passage 110 throughthe stud 102. A retinoid coating 114 provides biocompatibility ashereinabove discussed.

Turning to FIG. 6, there is shown a joint prosthesis 120 including afibrous spacer 122 held in position between bones 126,128 to be joinedby rigid fixation pins 130,132.

The spacer 122 may include a biodegradable polymer, co-polymermixtureand/or composite such as described in U.S. Pat. No. 6,007,580 andincluding a retinoid as herein described to improve biocompatibility.

Typically, the amount of retinoid employed represents 0.001% to 50%,more typically from 0.01 to 20%.

The retinoid may be either naturally occurring or a synthetic retinoidsuch as a retinoic acid receptor (RAR) agonist.

Naturally occurring retinoids suitable for use in the present inventionincludes naturally occurring retinoids such as Vitamin A (retinol),Vitamin A aldehyde (retinal), Vitamin A acid (retinoic acid) and theirsynthetic and natural congeners. These would include but not be limitedto the isomers all trans; 9-cis; 11-cis; 13-cis; 9, 11-dicis, and 11,13-dicis as well as physiologically compatible ethers, esters, amidesand salts thereof. the 7,8-dihydro and 5,6-dihydro congeners as well asetretinate are also acceptable for the invention.

Compounds that intrinsically or upon metabolism possess the physiologicproperties of retinoids are also included within the scope of thisinvention. These would include synthetic and natural retinoid compoundshaving affinity to nuclear retinoic acid receptors (RARs) and retinoid Xreceptors (RXRs).

Other synthetically prepared retinoids are also well known in the art.For example, see U.S. Pat. No. 5,234,926 which is incorporated here byreference thereto in its entirety which discloses methods ofsynthesizing disubstituted acetylenes bearing heteroaeromatic andheterobicyclic groups with a selective activity as RAR agonists. U.S.Pat. No. 4,326,055 is incorporated herewith by reference thereto in itsentirety for disclosing methods for synthesizing 5, 6, 7, 8-tetrahydronaphthal and indanyl stilbene derivatives with retinoid-like activity.

Examples of synthetic agonists suitable for use in the practice of thisinvention are ethyl6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate (Compound 168) and6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinic acid (Compound 299),whose synthesis is disclosed in U.S. Pat. No. 5,234,926 as Examples 6and 24, respectively; andp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoicacid (Compound 183), whose synthesis is disclosed in U.S. Pat. No.4,326,055, and2-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthaleen-2-yl)propen-1-yl]thiophene-4-carboxylicacid (Compound 701), whose synthesis is disclosed in U.S. Pat. No.5,324,840, Example 11.

Alternatively, the sclera plug 10, while being generally homogeneous,may include a film 50 of retinoid thereon in order to improvebiocompatibility in a manner similar to the improved biocompatibility ofa non-bioerodible device 42 such as shown in FIG. 3.

Accompanying the hereinabove described devices is a method in accordancewith the present invention for improving the biocompatibility of animplant in tissue which includes the step of providing a therapeuticagent, providing a carrier sized for insertion into the tissue in whichthe release of a therapeutic agent is desired, incorporating thetherapeutic agent into a carrier in a manner enabling the time releasedof the therapeutic agent and incorporating the retinoid into the carrierin an amount effective for improving the biocompatibility of a carrierin the tissue. This method, of course, corresponds to the device 10shown in FIGS. 1 and 2.

Correspondingly, a method in accordance with the present inventionrelating to the device 42 shown in FIG. 3 include combining the retinoid40 with the prosthesis 42. This method may include the deposition of afilm 40 on the prosthesis 42 or imbedding the retinoid into surface 44of the prosthesis. All of the hereinabove recited retinoids may be usedin accordance with the method of the present invention.

The following example illustrates the effectiveness of the method anddevices of the present invention. It should be appreciated that theexample is set forth herein for the purpose of illustration only and isnot to be regarded as limiting to any of the specific materials ormethods disclosed.

EXAMPLE 1

An implantable device 10 was prepared as follows:

Retinal plugs were manufactured from poly(D,L)lactic acid (PLA) with anintrinsic viscosity of 0.6DL/G. The retinoid 6-[(4,4-dimethylthiochroman-6-yl) ethynl] nicotinic acid (AGN190299) was mixed withpolymer in a three-dimensional mixer. The mixture was then extruded at85° C. into a homogeneous rod. The retinoid was incorporated into thepolymeric plug at a concentration of 10%. The extruded plug was then cutto a length of 3.0 mm and had a diameter of 1.5 mm. A 0.5 mm hole wasdrilled into the distal end of the plug to allow for suture fixation tothe sclera. Placebo plugs containing no retinoid were also manufacturedto the same dimensions. The average weight of the plugs was 8 mg. Allplugs were sterilized by gamma irradiation at 1 Mrad.

The plugs were then implanted into pigmented rabbits as shown in FIG. 2.The rabbit eyes were vitrectomized and the retinal plugs with or withoutincorporated retinoid were inserted through a sclerotomy 3 mm posteriorto the corneoscleral limbus. The plugs were then fixated with the sutureused to close the sclerotomy. An intravitreal injection of 500,000 humanRPE cells was given to simulate traction retinal detachment. The rabbitswere sacrificed at 28 days and histopathology was done.

These observed results are shown in FIG. 7 for the placebo plug and inFIG. 8 for the plug 10 including the retinoid as hereinabove described.

FIG. 7 is a drawing showing the encapsulation of a placebo plug 28 daysafter insertion into the vitreous through the sclera. The plug iscomprised of polylactic acid. The plug disappears during the processingof the eye (A). The tissues surrounding the plug were stained with PASand show a fibrous capsule surrounding the area (B) where the placebowas previously located. The capsule that surrounded the polylactic acidplug shows a very prominent inflammatory response with inflammatory cellinfiltration (C).

FIG. 8 is a drawing showing the encapsulation of a retinoid containingplug 28 days after insertion. The polylactic acid plug contain 10% byweight of the retinoid 6-[(4,4-dimethyl thiochroman-6-yl) ethynyl]nicotinic acid (AGN190299). The plug disappears in the processing of theeye (A). The tissues surrounding the retinoid containing plug werestained with PAS. The figure shows that the capsule surrounding theAGN190299 plug (B) has very little fibrous inflammation (C).

Although there has been hereinabove described a particular arrangementof implantable devices and methods in accordance with the presentinvention, for the purpose of illustrating the manner in which theinvention may be used to advantage, it should be appreciated that theinvention is not limited thereto. Accordingly, any and allmodifications, variations or equivalent arrangements which may occur tothose skilled in the art, should be considered to be within the scope ofthe present invention as defined in the appended claims.

What is claimed is:
 1. An implantable device for providing systemic orlocal release of a therapeutic agent in tissue, the device comprising: atherapeutic agent; an implant sized for insertion into tissue in whichsystemic or local release of the therapeutic agent is desired, saidimplant including means for providing controlled release of thetherapeutic agent wherein said means comprises a biodegradable polymer;and a retinoid means, separate from the therapeutic agent andhomogeneously distributed throughout the implant, for improvingbiocompatibility of the implant in the tissue.
 2. The implantable deviceaccording to claim 1 wherein said implant comprises a plug.
 3. Theimplantable device according to claim 1 wherein said implant comprises asclera plug.
 4. The implantable device according to claim 1 wherein saidimplant comprises a cardiac valve component.
 5. The implantable deviceaccording to claim 1 wherein said implant comprises a stent.
 6. Theimplantable device according to claim 1 wherein said implant comprisesan endovascular stent.
 7. The implantable device according to claim 1wherein said implant comprises a stud.
 8. The implantable deviceaccording to claim 1 wherein said implant comprises a prosthesis.
 9. Theimplantable device according to claim 1 wherein said implant comprises ajoint prosthesis.